The group I mGluRs (mGluR1 and mGluR5) are predominantly postsynaptic mGluRs that are coupled to phospholipase C, release of intracellular Ca2+, and activation of a variety of intracellular signaling molecules. PKC phosphorylation of mGluR5 has been known to affect Ca2+ signaling and receptor desensitization for some time, but rigorous studies on the direct phosphorylation of mGluR5 havent been conducted. Therefore, we are investigating the phosphorylation of mGluR5 and have identified several specific residues that are phosphorylated by protein kinase C. These PKC sites are located within the proximal one-third of the mGluR5 C-terminal domain. One phosphorylation site, Ser839, determines the regulation of intracellular calcium oscillations in response to mGluR5 activation. A second phosphorylation site that we have identified, Ser901, inhibits the binding of the protein calmodulin to mGluR5 and decreases mGluR5 surface expression. In parallel studies on the presynaptic receptor, mGluR7, we find that PKC phosphorylation of Ser862 inhibits calmodulin binding, and increases receptor surface expression. Therefore, we find a common mechanism to rapidly modify mGluR surface expression in response to increases in Ca2+, PKC activity, and changes in calmodulin binding; however, the changes in surface expression depend on receptor subtype and likely additional receptor subtype-specific binding proteins that are disrupted by calmodulin binding. These studies precisely defining the phosphorylation of mGluRs by PKC will allow us to study the functional consequences of glutamate receptor phosphorylation and the regulation of intracellular signaling and receptor trafficking.